Several old world alphaviruses, including the Sindbis-group viruses, Ross River virus, O'nyong-nyong and Chikungunya, are associated with outbreaks of acute and persistent arthritis/arthralgia in humans (reviewed in Johnston, R. E. and C. J. Peters. 1996. Alphaviruses, p. 843-898. In B. N. Fields, D. M. Knipe, and P. M. Howley (eds.), Fields Virology. Lippincott-Raven, Philadelphia). Chikungunya and O'nyong-nyong have caused massive epidemics of acute, debilitating arthralgia in Africa and Asia (Id.). Ross River virus, also known as epidemic polyarthritis, is endemic to Australia (Aaskov et al., (1985) Aust. J. Exp. Biol. Med. Sci. 5:587; Johnston, R. E. and C. J. Peters. 1996. Alphaviruses, p. 843-898. In B. N. Fields, D. M. Knipe, and P. M. Howley (eds.), Fields Virology. Lippincott-Raven, Philadelphia; Tai et al., (1993) Med. J. Aust. 158:522), and caused a major epidemic that swept the South Pacific Islands in 1979, affecting 50,000 people on the Island of Fiji (Aaskov et al., (1981) Am. J. Trop. Med. Hyg. 30:1053). Sindbis-group alphaviruses, including Ockelbo, Karelian fever virus, and GirdwoodS.A. are associated with acute and persistent arthralgia in Northern Europe and South Africa (Malherbe et al., (1963) S. Afr. Med. J. 37:547; Skogh et al., (1982) Lancet i:795; Tesh et al., (1982) Ann. Rev. Med. 33:31). Ockelbo disease; one of the best characterized of the Sindbis-group alphavirus arthralgias, is often incapacitating (Johnston, R. E. and C. J. Peters. 1996. Alphaviruses, p. 843-898. In B. N. Fields, D. M. Knipe, and P. M. Howley (eds.), Fields Virology. Lippincott-Raven, Philadelphia; Tesh et al., (1982) Ann. Rev. Med. 33:31), and one study found that symptoms lasted for months to years in 31% of patients (Niklasson et al., (1986) Lancet 1:1039). Symptoms include arthralgia in one or more joints, including large joints such as the knee, hip, and elbow (reviewed in Johnston, R. E. and C. J. Peters. 1996. Alphaviruses, p. 843-898. In B. N. Fields, D. M. Knipe, and P. M. Howley (eds.), Fields Virology. Lippincott-Raven, Philadelphia; Tesh et al., (1982) Ann. Rev. Med. 33:31). Pain within or around tendons is also a common trait of Sindbis-group virus infections (Tesh et al., (1982) Ann. Rev. Med. 33:31). Rubella virus, another member of the family Togaviridae that is distantly related to the alphaviruses, is also associated with acute and persistent arthritis in humans (reviewed in Wolinsky, J. S. 1996. Rubella, p. 899-929. In B. N. Fields, D. M. Knipe, and P. M. Howley (eds.), Field's Virology. Lippencott-Raven, Philadelphia).
Mechanisms underlying Togavirus induced arthralgia/arthritis are not clearly understood, though direct viral replication within or around the affected joints may contribute to disease (reviewed in Tesh et al., (1982) Ann. Rev. Med. 33:31). Ross River virus antigen has been detected in cell aspirates from the joints of acutely infected individuals (Fraser et al., (1983) J. Clin. Path. 36:1256). Furthermore, patients suffering from persistent arthralgia following Ockelbo virus infection often have high levels of Ockelbo virus specific IgM, which suggests that the virus may persistently infect these individuals (Niklasson et al., (1988) J. Infect. Dis. 157:832).
Understanding of the mechanisms leading to alphavirus mediated arthritis/arthralgia in humans has been hampered by the lack of a small animal model. Sindbis-group alphaviruses, Semliki Forrest virus, and Ross River virus replicate in bone associated connective tissue in neonatal mice, however skin and muscle are also major sites of viral replication (Klimstra et al., (1999) J. Virol. 73:10387; Murphy et al., (1970) Lab. Invest. 22:318; Murphy et al., (1973) Journal of Infectious Disease 127:129; Trgovcich et al., (1996) Virol. 224:73). Furthermore, infection of neonatal animals with these viruses results in rapidly fatal disease (Id.). This generalized pattern of replication and lethal outcome in neonatal mice has limited their usefulness as a model of bone and/or joint replication by arthralgia associated alphaviruses.
The present invention addresses a need in the art for improved alphavirus vectors and methods of administering the same.